A Convenient and Efficient Synthesis of HeteroaromaticHydrazone Derivatives via Cyclization of Thiosemicarbazone

with x-Bromoacetophenone

Weiwei Liu,a* Chuanzhou Tao,a Lijuan Tang,a Jie Li,a Yan Jin,a

Yueqiang Zhao,a and Hongwen Hub

aSchool of Chemical Engineering, Huaihai Institute of Technology, Lianyungang 222005, People’s

Republic of ChinabDepartment of Chemistry, Nanjing University, Nanjing 210093, People’s Republic of China

*E-mail: liuww323@yahoo.com.cn

Received March 19, 2010

DOI 10.1002/jhet.585

Published online 22 December 2010 in Wiley Online Library (wileyonlinelibrary.com).

The synthesis of hydrazone derivatives containing thiazole unit was achieved with condensation ofthiosemicarbazones and x-bromoacetophenone at room temperature. This mild, convenient, and efficientmethod affords the desired products with good to excellent yields. Their structures have been deter-

mined by X-ray diffractional analysis, 1H-NMR, MS, elemental analysis, and IR. Thiosemicarbazoneswere prepared by the condensation of thiosemicarbazide with aldehydes or ketones.

J. Heterocyclic Chem., 48, 361 (2011).

INTRODUCTION

Thiosemicarbazones and their derivatives are impor-

tant compounds in organic and medicinal chemistry

due to their biological properties including antitumor

[1], antifungal [2], antibacterial [3], antimalarial [4],

antifilarial [5], antiviral, and anti-HIV activities [6].

Thiosemicarbazones, especially those derived from het-

eroaromatic aldehydes or ketones have been exten-

sively studied. It is found that their structural pi-deloc-

alization of charge and configurational flexibility of

their molecular chain can give rise to a variety of reac-

tion manners.

As part of our studies on thiocarbonyl chemistry [7],

the reactivity of heteroaromatic aldehyde- and ketone-

derived thiosemicarbazones were further investigated.

Chemical compounds with biological activity are often

derived from heterocyclic structures. Heterocycles are

an important class of scaffolds that are found in natural

products such as vitamins, hormones, antibiotics, as well

as pharmaceuticals, herbicides, and dyes. Herein, we

report an efficient and convenient method to synthesize

a new class of thiosemicarbazones that contain thiazole

heterocyclic ring. These novel compounds were

expected to exhibit biological activity in the near future.

The structures of products have also been fully charac-

terized by infrared spectroscopy (IR), 1H nuclear mag-

netic resonance (1H-NMR), mass spectrometry (MS),

elemental analysis, and single-crystal X-ray diffraction

analysis.

RESULTS AND DISCUSSION

Initially, thiosemicarbazones 2a were synthesized by

treating heterocyclic thioaldehydes 1a with potassium hy-

droxide and an equimolar quantity of thiosemicarbazide

in the cosolvent of anhydrous ethanol and dimethylsulf-

oxide (DMSO) [8]. The desired thiosemicarbazones 2b–

2e also can be readily formed under the acid or neutral

condition. The results are summarized in Table 1.

The structures of 2a–2e were unambiguously charac-

terized by spectroscopy (1H-NMR, IR, and MS), ele-

mental analysis, and further confirmed by X-ray diffrac-

tional analysis [9] of 2a. The Oak Ridge Thermal Ellip-

soid Plot (ORTEP) drawing and cell packing diagram

are given in Figure 1.

Subsequently, we treat heteroaromatic thiosemicarba-

zones 2a with x-bromoacetophenone in anhydrous etha-

nol. To our surprise, a novel compound (3a) with thia-

zole scaffold was formed. The reaction proceeds

smoothly at room temperature and good yield (62%)

was obtained. Single-crystal X-ray diffraction analysis

[10] of 3a was measured, and the ORTEP drawing and

cell packing diagram are given in Figure 2.

Then, we examine whether the same reaction system

can be applied to other heteroaromatic thiosemicarba-

zones (entries 2–5). It is found that both heteroaromatic

aldehyde-derived and heteroaromatic ketone-derived thi-

osemicarbazones can be smoothly converted to the

desired products with good to excellent yields (61–

90%). The results were summarized in Table 2. It is

VC 2010 HeteroCorporation

March 2011 361

noteworthy that the present reaction was accomplished

under mild conditions and the method is operationally

simple with satisfactory yields. The structures of 3a,

4b–4e have been characterized by spectroscopic (1H-

NMR, IR, and MS) and elemental analysis.

A plausible mechanism was proposed in Scheme 1.

The bromine of x-bromoacetophenone was substituted

to form imide salt 5. The protolysis reaction of 5 gave 6

followed by cyclization leading to 4-hydroxyl-4,5-dihy-

drothiazole salt 7. The salt releases H2O to afford thia-

zole salt 3a and 4 followed by losing HBr to form

thiazole ring. Since indolizinyl moiety has the strong

conjugation ability, 3-formyl-2-phenylindolizine thiose-

micarbazone (2a) can react with x-bromoacetophenone

to afford thiazole salt 3a. When referred to other thiose-

micarbazone (2b–2e), the final step is to release HBr to

give products (4b–4e) with thiazole rings.

To conclude, in the present study, we report a conven-

ient and efficient method to synthesize a series of novel

thiosemicarbazone derivatives that contain thiazole heter-

ocyclic ring. Given the fact that many thiosemicarbazone

derivatives have exhibited biological activity, we antici-

pate that these new compounds described in the present

report would be valuable for pharmaceutical research.

EXPERIMENTAL

Melting points are uncorrected. IR spectra were recorded on a

Nicolet FTIR 5DX spectrometer in KBr with absorption in cm�1.1H-NMR spectra were recorded on a Bruker ACF-300 spectrome-ter, J values are in hertz. Chemical shifts are expressed in d down-field from internal tetramethylsilane. Mass spectra were obtainedon a ZAB-HS mass spectrometer at 70 eV. Elemental analytical

were performed on a Foss Heraeus CHN-O-Rapid analyzer.Preparation of 3-formyl-2-phenylindolizine thiosemicar-

bazone (2a). A solution of 2-phenyl-3-thioformylindolizine (1a;0.24 g, 1 mmol) and thiosemicarbazide (0.09 g, 1 mmol) in anhy-

drous ethanol (50 mL) was stirred, after adding potassium hy-droxide (0.06 g, 1.1 mmol), DMSO (5 mL) was added dropwise.The mixture was refluxed at 80�C for 6 h [monitored by thinlayer chromatography (TLC)], the resulting mixture was cooledand poured into ice water, filtered, purified by alumina chroma-

tography eluted with the mixture of petroleum ether and ethyl ac-etate in gradient to afford 2a.

General procedure for preparation of thiosemicarbazone

(2b–2d). ‘A solution of 2-formylfuran (1b; 0.29 g, 3 mmol) andthiosemicarbazide (0.27 g, 3 mmol) in 50% ethanol (20 mL) was

stirred, 0.8-mL glacial acetic acid was added. The mixture wasrefluxed at 80�C for 2 h (monitored by TLC), the resulting mix-ture was cooled and poured into ice water, filtered, purified byrecrystallization from anhydrous ethanol to afford 2b. Under

Table 1

Results of reactions of thiosemicarbazide with aldehydes, thioaldehydes, and ketones.

Entry Ar R X Solvent Time (h) Product Yield (%)

1 2-Phenylindolizin-3-yl H S EtOH/DMSO 6 2a 78

2 Furan-2-yl H O EtOH/H2O 2 2b 70

3 Thiophen-2-yl H O EtOH/H2O 5 2c 73

4 Indol-3-yl H O EtOH/H2O 3 2d 88

5 Phenyl O EtOH 4 2e 70

Figure 1. Molecular structure of 2a. Figure 2. Molecular structure of 3a.

362 Vol 48W. Liu, C. Tao, L. Tang, J. Li, Y. Jin, Y. Zhao, and H. Hu

Journal of Heterocyclic Chemistry DOI 10.1002/jhet

these conditions, reaction of 1b–1d was similarly conducted togive the corresponding thiosemicarbazone 2b–2d.

1-Phenyl-2-[1,2,4]triazol-1-ylethanone thiosemicarbazone

(2e). A solution of 1-phenyl-2-[1,2,4]triazol-1-ylethanone (0.56g, 3 mmol) and thiosemicarbazide (0.27 g, 3 mmol) in anhy-drous ethanol (20 mL) was stirred, 0.2-mL glacial acetic acidand catalyst levels pyridine was added. The mixture wasrefluxed at 80�C for 4 h (monitored by TLC), the resulting

mixture was cooled and poured into ice water, filtered, purifiedby recrystallization from anhydrous ethanol to afford 2e.

General procedure for the cyclization of 2 and x-bro-moacetophenone to prepare 3a or 4b–4e. A solution of 2-phenyl-3-thioformylindolizine thiosemicarbazone (2a; 0.12 g,

0.40 mmol), x-bromoacetophenone (0.085 g, 0.40 mmol) inanhydrous ethanol (10 mL) was stirred at room temperature,until all the thiosemicarbazone had disappeared (monitored byTLC). The deposit was filtered, purified by recrystallizationfrom 95% ethanol to afford 3a. Under these conditions, reac-

tion of 2b–2e was similarly conducted to give the correspond-ing cyclization compound 4b–4e.

3-Formyl-2-phenylindolizine thiosemicarbazone (2a). Yellowcrystals, Yield 78%, m.p. 155�C; IR (KBr): 3510, 3384, 3232,

3139, 3027.8, 1600, 1583, 1537, 1500, 1454, 1096, 834 cm�1;1H-NMR (300 MHz, CDCl3): d 6.41 (br, s, 1H, ANH2), 6.67(s, 1H, indolizin-3-yl C1AH), 6.86–6.90 (m, 2H, indolizin-3-ylC6AH, ANH2), 7.04–7.10 (m, 1H, indolizin-3-yl C7AH),7.44–7.58 (m, 6H, Ph, indolizin-3-yl C8AH), 8.10 (s, 1H,

¼¼CHA), 9.14 (s, 1H, ANHA), 9.21 (d, J ¼ 7.0 Hz, 1H, indo-lizin-3-yl C5AH). Anal. Calcd for C16H14N4S: C, 65.31; H,4.76; N, 19.05. Found: C, 65.45; H, 4.95; N, 19.10. MS (EI):m/z 276 (58.9), 249 (24.7), 218 (51.3), 193 (100), 165 (35.3),115 (29.6), 83 (30.8), 51 (28.9).

2-Formylfuran thiosemicarbazone (2b). Yellowish browncrystals, yield 70%, m.p. 154–156�C (lit. 152–154�C) [8].

2-Formylthiophene thiosemicarbazone (2c). Light browncrystals, yield 73%, m.p. 184–186�C (lit. 185–186�C) [8].

3-Formyl-1H-indole thiosemicarbazone (2d). Light pink

crystals, yield 88%, m.p. 232–234�C; IR (KBr): 3448, 3311,3230, 3145, 3039, 1613, 1582, 1550, 1518, 1441, 1200, 751cm�1; 1H-NMR (300 MHz, DMSO-d6): d 7.10–7.21 (m, 2H,indol-3-yl C6-H, indol-3-yl C7AH), 7.42 (br, s, 1H, ANH2),

7.43 (d, J ¼ 7.9 Hz, 1H, indol-3-yl C8AH), 7.82 (d, J ¼ 2.7Hz, 1H, indol-3-yl C2AH), 8.03 (br, s, 1H, ANH2), 8.23 (d, J

¼ 7.7 Hz, 1H, indol-3-yl C5AH), 8.31(s, 1H, ¼¼CHA), 11.18(s, 1H, ANHA), 11.61 (s, 1H, indol-3-yl nitrogen proton).Anal. Calcd for C10H10N4S: C, 55.04; H, 4.59; N, 25.69.

Found: C, 55.10; H, 4.55; N, 25.62. MS (EI): m/z 218 (Mþ,2.4), 201 (16), 143 (61.2), 142 (100), 115 (28.9), 89 (10.9).

1-Phenyl-2-[1,2,4]triazol-1-ylethanone thiosemicarbazone(2e). Colorless crystals, yield 70%, m.p. 157–159�C ; IR (KBr):3373, 3264, 3173, 3073, 2986, 1644, 1619, 1603, 1510, 1492,

1448, 1270, 844, 745, 676 cm�1; 1H-NMR (300 MHz, DMSO-d6): d 5.73 (s, 2H, ACH2A), 7.37–7.95 (m, 5H, PhH), 8.11 (s,1H, ANH2), 8.52 (s, 1H, 1H-1, 2, 4-triazol-1-yl proton), 8.65 (s,1H, ANH2), 8.68 (s, 1H, 1H-1, 2, 4-triazol-1-yl proton), 10.96(s, 1H, ANHA). Anal. Calcd for C11H12N6S: C, 50.77; H, 4.62;

N, 32.31. Found: C, 50.85; H, 4.67; N, 32.30. ; MS (EI): m/z243 (1.4), 178 (15.9), 103 (100), 77 (44.2), 69 (10.5).

N-(4-phenyl-thiazol-2-yl)-3-formyl-2-phenylindolizine hydra-zone hydrobromic acid (3a). Green crystals, yield 62%, m.p.122–124�C; IR (KBr): 3333, 2853, 1625, 1590, 1533, 1496,

1456, 764, 697 cm�1; 1H-NMR (300 MHz, CDCl3): d 6.72 (s,1H, indolizin-3-yl C1AH), 6.90–7.01 (m, 1H, indolizin-3-ylC6AH), 7.10–7.21 (m, 1H, indolizin-3-yl C7AH), 7.37–7.88 (m,12H, indolizin-3-yl C8AH, phenyl and thiazole ring proton);

8.41 (s, 1H, ¼¼CAH), 9.31 (d, J ¼ 8.2 Hz, 1H, indolizin-3-ylC5AH), 12.61 (s, 1H, ANHA), 13.87 (s, 1H, ANþHA). Anal.Calcd for C24H21BrN4OS: C, 58.42; H, 4.26; N, 11.36. Found:

Table 2

Reactions of heteroaromatic thiosemicarbazones 2 with x-bromoacetophenone.

Entry Ar R Time (min) Product Yield (%)

1 2-Phenylindolizin-3-yl H 12 3a 62

2 Furan-2-yl H 30 4b 87

3 Thiophen-2-yl H 20 4c 66

4 Indol-3-yl H 30 4d 90

5 Phenyl 30 4e 61

Scheme 1

March 2011 363A Convenient and Efficient Synthesis of Heteroaromatic Hydrazone Derivatives viaCyclization of Thiosemicarbazone with x-Bromoacetophenone

Journal of Heterocyclic Chemistry DOI 10.1002/jhet

C, 58.50; H, 4.42; N, 11.26. MS (EI): m/z 394 [(M-HBr-H2O)þ,

2.9], 219 (92), 218 (100), 192 (2.2), 176 (96.6), 134 (56.6).N-(4-phenyl-thiazol-2-yl)-2-formylfuran hydrazone (4b). Brown-

ish yellow crystals, yield 87%, m.p. 136–138�C; IR (KBr):3117, 3141, 3065, 1619, 1603, 1561, 1486, 760, 691 cm�1;1H-NMR (300 MHz, DMSO-d6): d 6.59–6.62 (m, 1H, furan-2-yl C4AH), 6.81 (d, J ¼ 3.3 Hz, 1H, furan-2-yl C3AH), 7.23–7.93 (m, 9H, thiazole ring and phenyl proton, furan-2-ylC5AH, ¼¼CAH, ANHA). Anal. Calcd for C14H11N3OS: C,62.45; H, 4.09; N,15.61. Found: C, 62.53; H, 4.05; N,15.77.

MS (EI): m/z 269 (Mþ, 16.8), 176 (100), 134 (62.6).N-(4-phenyl-thiazol-2-yl)-2-formylthiophene hydrazone (4c).

Light brown crystals, yield 66%, m.p. 202–203�C; IR (KBr):3302, 3099, 3055, 1602, 1561, 1521, 1505, 1490, 768, 748,740, 722, 706, 683 cm�1; 1H-NMR (300 MHz, CDCl3): d 6.80

(s, 1H, thiazole ring proton), 7.00–7.90 (m, 8H, thiophen-2-yland phenyl proton), 7.97 (s, 1H, ACH¼¼NA), 8.20 (br, s, 1H,ANHA). Anal. Calcd for C14H11N3S2: C, 58.95; H, 3.86; N,14.74.Found: C, 59.01; H, 3.96; N, 14.65. MS (EI): m/z 285

(Mþ, 15.8), 176 (100), 134 (83.5), 110 (4.4), 77 (2.5).N-(4-phenyl-thiazol-2-yl)-2-formyl-1H-indole hydrazone (4d).

Light purple crystals, yield 90%, m.p. 185–187�C; IR (KBr):3292, 3103, 2943, 1625, 1608, 1574, 1531, 1491, 749, 735675 cm�1; 1H-NMR (300 MHz, DMSO-d6): d 7.15–7.52 (m,

8H, thiazole ring and phenyl proton, indol-3-yl C6AH, indol-3-yl C7AH), 7.78 (s, 1H, ANHA), 7.85–7.95 (m, 2H, indol-3-ylC8AH, indol-3-yl C2AH), 8.23–8.35 (m, 2H, indol-3-yl C5AH,¼¼CHA), 11.61 (s, 1H, indol-3-yl nitrogen proton). Anal. Calcdfor C18H14N4S: C, 67.92; H, 4.40; N, 17.61. Found: C, 67.93;

H, 4.32; N, 17.66. MS (EI): m/z 318 (Mþ, 0.5), 176 (100), 142(59.6), 134 (38.4), 115 (7.4), 89 (5.2).

N-(4-phenyl-thiazol-2-yl)-x-(1, 2, 4-triazol-1-yl)acetophe-none hydrazone (4e) Light yellow crystals, yield 61%, m.p.212–214�C; IR (KBr): 3165, 3096, 3081, 2656, 1598, 1583,

1503, 1444, 749, 688 cm�1; 1H-NMR (300 MHz, DMSO-d6):d 5.74 (s, 2H, ACH2A); 7.33–7.89 (m, 11H, thiazole ring andphenyl proton), 7.97 (s, 1H, 1H-1, 2, 4-triazol-1-yl proton),8.74 (s, 1H, 1H-1, 2, 4-triazol-1-yl proton). Anal. Calcd for

C19H16N6S: C, 58.95; H, 3.86; N, 14.74. Found: C, 59.01; H,3.96; N, 14.65. MS (EI): m/z 291 (22.7), 262 (18.8), 176 (9.4),134 (59.9), 103 (100), 77 (66.5), 69 (13.9).

Acknowledgments. The authors are grateful to the NationalNatural Science Foundation of China (No. 20672090), the SixKinds of Professional Elite Foundation of Jiangsu Province(No. 07-A-024), the Science and Technology Critical Project

Foundation of Lianyungang Municipality (CG0803-2), and theNatural Science Foundation of Jiangsu Education Department(08KJB150002).

REFERENCES AND NOTES

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[3] Gupta, M. K.; Sachan, A. K.; Pandeya, S. N. Asian J Chem

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[5] Klayman, D. L.; Lin, A. J.; McCall, J. W.; Wang, S. Y.;

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soz, S.; Otuk, G.; Ulkuseven, B. Folia Microbiol 2007, 52, 15.

[7] (a) Liu, W. W.; Zhao, Y. Q.; Pu, Y. Q.; Xu, R. B.; Hu, H.

W. Chin J Org Chem 2005, 25, 838; (b) Liu, W. W.; Zhao, Y. Q.;

Xu, R. B.; Tang, L. J.; Hu, H. W. Chin J Chem 2006, 24, 1472; (c)

Liu, W. W.; Tang, L. J.; Zeng, Y. X.; Wang, L.; Zhao, Y. Q.; Chen,

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[8] (a) Anderson, F. E.; Duca, C. J.; Scudi, J. V. J Am

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[9] Crystal data for 2a: 2(C16H14N4S)�C2H6CO; M ¼ 646, Yel-

low single crystals, 0.20 � 0.20 � 0.30 mm3, triclinic, space group

P1, a ¼ 11.572 (8), b ¼ 11.845 (8), c ¼ 13.173 (8) A, a ¼ 92.56 (3),

b ¼ 110.61 (4), c ¼ 102.57 (4)�, V ¼ 1635 (2) A3, Z ¼ 2, Dc ¼1.318 mg m�3. F (000) ¼ 682, l (MoKa) ¼ 0.206 mm�1. Intensity

data were collected on Bruker SMART APEX II with graphite mono-

chromated MoKa radiation (k ¼ 0.71073 A) using x scan mode with

1.9� < y < 25.0�. 5671 unique reflections were measured and 4302

reflections with I > 2r(I) were used in the refinement. Structure

solved by direct methods and expanded using Fourier techniques. The

final cycle of full-matrix least squares technique to R ¼ 0.0533 and

wR ¼ 0.1168.

[10] Crystal data for 3a: C24H21BrN4OS; M ¼ 493, Blackish

green single crystals, 0.42 � 0.36 � 0.20 mm3, monoclinic, space

group P21/n, a ¼ 6.1679 (12), b ¼ 11.1657 (18), c ¼ 32.640 (4) A, a¼ 90, b ¼ 91.708 (2), c ¼ 90�, V ¼ 2246.9 (6) A3, Z ¼ 4, Dx ¼1.459 mg m�3. F (000) ¼ 1008, l (MoKa) ¼ 1.946 mm�1. Intensity

data were collected on Bruker SMART APEX II with graphite mono-

chromated MoKa radiation (k ¼ 0.71073 A) using x scan mode with.

1.93� < y < 25.01�. 3904 unique reflections were measured and 2795

reflections with I > 2r(I) were used in the refinement. Structure

solved by direct methods and expanded using Fourier techniques. The

final cycle of full-matrix least squares technique to R ¼ 0.0661 and

wR ¼ 0.1554.

364 Vol 48W. Liu, C. Tao, L. Tang, J. Li, Y. Jin, Y. Zhao, and H. Hu

Journal of Heterocyclic Chemistry DOI 10.1002/jhet